The invention relates to a novel process for the preparation of robenidine and salts thereof of the general formula 
in which X denotes a halogen atom, utilizing hydrazine hydrate and a cyanogen halide are starting materials.
In Chemical Abstract No. 6745j to Shestakov et al., a process for preparing robenidine containing 14C and 3H isotopes is disclosed. Another reference disclosing robenidine compounds and their derivatives is U.S. Pat. No. 4,575,560 to Addor et al. The Addor reference discloses the use of such compounds as antiprotozoal agents, specifically anticoccidial agents, as well as insecticidal agents that exhibit antifeeding activity when applied to plants. However, in both of the above references, the intermediate diaminoguanidine salt that is formed must be separated off prior to further processing. Thus, these references disclose processes in which robenidine is prepared from a diaminoguanidine salt which has already been isolated.
As disclosed in a German patent reference (DE 19 33 112 A1 to American Cyanamid Co.), robenidine, 1, 3-bis [(4-chlorobenzylidene) amino] guanidine, and robenidine derivatives may be employed for controlling coccidiosis infections in poultry, and such compounds may act as active antimalaria agents for homeotherms. This reference discloses a process for preparing robenidine wherein dichlorobenzaldehyde or p-chlorobenzaldehyde is reacted with a diaminoguanidine salt, for example 1, 3-diaminoguanadine nitrate, in ethanol to give the desired product. A disadvantage of this process is the fact that the product is obtained in only moderate yield.
It was an object of the present invention to provide a xe2x80x9cone-potxe2x80x9d process for the preparation of robenidine wherein the desired product is obtained in excellent yield and purity.
It was a further object of the present invention to convert the diaminoguanidine salt produced in the first step of the process directly into the end product without isolation and purification of the intermediate.
Still another object of the present invention involves providing a process for producing robenidine and salts thereof in both a simple and economical manner.
These objects are achieved through a process for preparing robenidine and salts thereof, wherein the robenidine and its salts have the general formula 
and wherein X is a halogen atom. In this process, hydrazine hydrate is reacted with a cyano compound in a C1-4-alcohol or a C1-4-alcohol/water mixture as the solvent, to produce a diaminoguanidine. Subsequently, the diaminoguanidine is converted directly, without isolation, by reacting with a p-halobenzaldehyde in a C1-4-alcohol/water mixture as the solvent, to produce the robenidine and salts thereof of general formula I.
These and other objects of the present invention will be more fully understood from the following description of the invention.
According to the invention, the process is carried out such that in a first step, hydrazine hydrate is reacted with a cyano compound of the general formula
Yxe2x80x94CNxe2x80x83xe2x80x83II 
in which Y denotes a halogen atom or tosyl. This reaction takes place in a C1-4-alcohol or a C1-4-alcohol/water mixture as solvent or in an aprotic polar organic solvent and produces a diaminoguanidine of the general formula 
in which Y has the meaning stated above. This diaminoguanidine is converted directly, without isolation, by reacting in a second step with a p-halobenzaldehyde of the general formula 
(in which X denotes a halogen atom), in a C1-4-alcohol or a C1-4-alcohol/water mixture as solvent or in a mixture of an aprotic organic solvent and water, into the end product of the formula 
in which X denotes a halogen atom. The end product may also be a salt of the end product shown above in Formula I.
Y may be a halogen, for instance, fluorine, chlorine, bromine or iodine, or Y may be tosyl. In certain preferred embodiments, Y denotes chlorine, bromine or tosyl. Furthermore, the cyano compounds used in the first step may be cyanogen chloride, cyanogen bromide, or tosyl cyanide. In certain preferred embodiments, the cyano compound employed is cyanogen chloride.
The C1-4-alcohols used as solvents may be methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tertbutanol. In certain preferred embodiments, isopropanol is used as the solvent.
The aprotic polar solvents used may be ethers, glycol ethers or organic nitrogen compounds. The ethers used may be, for example, dioxane or tetrahydrofuran, and the glycol ethers used may be, for example, mono-, di-, tri- or polyethylene glycol ether. The organic nitrogen compounds used may be, for example, acetonitrile, propionitrile or dimethylformamide.
In certain embodiments, it is preferable to carry out the first step of the process in a C1-4-alcohol/water mixture. The mixing ratio (% by weight) for such an alcohol/water mixture may range from 1:1 to 15:1. In certain preferred embodiments, this mixing ratio ranges from 4:1 to 10:1.
The starting materials, the hydrazine hydrate and the cyano compounds, such as cyanogen chloride, are commercially available compounds.
The reaction of the first step may be carried out at a temperature of from xe2x88x9230xc2x0 to 50xc2x0 C., while certain preferred embodiments are carried out at a temperature of from xe2x88x9210xc2x0 to 30xc2x0 C. Other preferred embodiments may be carried out at a temperature of from 0xc2x0 to 20xc2x0 C.
X is a halogen atom such as fluorine, chlorine, bromine, or iodine. In certain preferred embodiments, X denotes chlorine or bromine, and in still other preferred embodiments, X is chlorine.
Accordingly, the p-halobenzaldehydes used may be, for example, p-chlorobenzaldehyde or p-bromobenzaldehyde. In certain preferred embodiments, p-chlorobenzaldehyde is used.
The process in the second step may be carried out at a temperature of from 50xc2x0 to 90xc2x0 C., while certain preferred embodiments are carried out at a temperature of from 65xc2x0 to 85xc2x0 C.
The second step may utilize the same C1-4-alcohols and the same aprotic polar organic solvents as in the first step. However, as described above, the second step can also be carried out in a mixture of water and an aprotic polar solvent. The ratio of water/aprotic polar organic solvent (% by weight) is advantageously 10:1 to 1:1, preferably 2:1 to 1:1.
In a particularly preferred embodiment, the solvent used in the first step is diluted with water prior to the second step, especially if no aqueous solvent was used in the first step.
The second step of the reaction or process may be carried out at a pH below 3, while certain preferred embodiments may be carried out at a pH of from 0.5 to 1.5. The pH may be established by the addition of a mineral acid, for example, hydrochloric acid, nitric acid, or sulfuric acid.
After a customary reaction time of from 0.5 to 3 h, the robenidine or a derivative thereof may be obtained, by customary work-up methods, as a salt in excellent yield and purity. Salts of robenidine or of robenidine derivatives which may be prepared according to the invention include, for example, the hydrohalide salts, such as the hydrochloride or hydrobromide salts.